Cancer is a general term used to describe diseases in which abnormal cells divide without control. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body. There are different types of cancers such as bladder cancer, breast cancer, colon cancer, rectal cancer, head and neck cancer, endometrial cancer, kidney (renal cell) cancer, leukemia, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, Non-Hodgkin's Lymphoma and melanoma. Currently there are many treatments available for cancer than ever before, including chemotherapy, radiation, surgery, hormonal therapy, immune therapy and gene therapy. Chemotherapy is the routinely used treatment against many types of cancer. The most widely used chemotherapeutic agents (the antineoplastic agents) include paclitaxel, docetaxel, doxorubicin, etoposide, carboplatin, cisplatin, topotecan and gemcitabine. These and other like antineoplastic agents have been successfully used for the treatment of different cancers. However, in due course of time, some cancer patients have been found to develop resistance to monotherapy involving use of such standard antineoplastic agents. Tolerance or resistance to a drug represents a major impediment to successful treatment. Such resistance is often considered as either intrinsic (i.e. present at the onset of treatment) or acquired (i.e. occurs during courses of chemotherapy). A study involving exposure of human non-small cell lung cancer cells (NCI-H460) to gradually increasing concentrations of doxorubicin reported appearance of a new cell line (NCI-H460/R) that was resistant to doxorubicin (96.2-fold) and cross-resistant to etoposide, paclitaxel, vinblastine and epirubicin (J. Chemother., 2006 February; 18(1) 66-73). In another study describing prevalence of in vitro chemotherapy resistance in non-small cell lung cancer (NSCLC) tumor cultures, extreme drug resistance or intermediate drug resistance to a number of antineoplastic agents including cisplatin, doxorubicin, etoposide, gemcitabine, navelbine, paclitaxel, taxotere and topotecan has been reported (Ann. Thorac. Surg. 2006 February; 81(2):440-6; discussion 446-7). Gemcitabine was considered to be the most clinically active drug for the treatment of pancreatic cancer, however it failed to significantly improve the condition of pancreatic cancer patients because of the pre-existing or acquired chemo resistance of most of the tumor cells to the drug (Oncogene 2003 May 22; 22(21): 3243-51). Another problem observed or prevalent in the cancer treatment is the severe toxicity associated with most of the antineoplastic agents. Incidence of severe side effects such as cardiac toxicity in case of drugs like doxorubicin has been reported in J Egypt Natl Canc Inst. 2005 Dec—17(4)—291-300. Despite the incidence of resistance and severe toxicity associated with the conventional antineoplastic agents e.g. gemcitabine, paclitaxel, these agents will continue to be important in the cancer treatment because they have the ability to reduce tumor mass. In order to improve the response rate and prevent toxicity associated with the conventional antineoplastic agents, new therapeutic approaches are being evaluated. One such approach is directed to a protocol involving combining different anticancer agents having different biological mechanism (Jekunen et al., Br. J. Cancer, 69, 299-306 (1994); Yeh et al., Life Sciences, 54, 431-35 (1994)). An optimal combination chemotherapy protocol may result in increased therapeutic efficacy, decreased host toxicity, and minimal or delayed drug resistance. When drugs with different toxicities are combined, each drug can be used at its optimal dose, helping minimise intolerable side effects, as reported for the combination of capecitabine and docetaxel in Oncology (Williston Park). 2002 October; 16:17-22. Some of the antineoplastic agents have been found to be synergistically effective when used in combination with other anticancer agents than when used as a monotherapy. For example, cyclophosphamide and 5-fluorouracil act synergistically in ovarian clear cell adenocarcinoma cells as reported in Cancer Lett. 2001 Jan. 10; 162(1):39-48. Combination chemotherapy can also be advantageously used for treating cancers in advanced stages which are difficult to treat with monotherapy, radiation or surgical treatment, for example, a combination of paclitaxel and gemcitabine has been reported for the treatment of metastatic non-small cell lung cancer (Cancer, 2006 Sep. 1; 107(5):1050-4).
Recently, combination of one or more standard antineoplastic agents such as paclitaxel, cisplatin etc. with a molecularly targeted anticancer agent for the treatment of cancer has been tried out to improve drug response rates and to address resistance to the antineoplastic agents. Molecularly targeted agents e.g. imatinib mesylate, flavopiridol etc. modulate proteins such as kinases whose activities are more specifically associated with cancerous cells. Researches over a long period of time have proven that the members of the cyclin-dependent kinase (CDK) family play key roles in various cellular processes. There are 11 members of the CDK family known till now. Among these, CDK1, 2, 3, 4, and 6 are known to play important roles in the cell cycle (Cyclins and cyclin-dependent kinases: theme and variations. Adv Cancer Res. 1995; 66:181-212). CDKs are activated by forming noncovalent complexes with cyclins such as A-, B-, C-, D- (D1, D2, and D3), and E-type cyclins. Each isozyme of this family is responsible for particular aspects (cell signaling, transcription, etc) of the cell cycle, and some of the CDK isozymes are specific to certain kinds of tissues. Aberrant expression and overexpression of these kinases are evidenced in many disease conditions. A number of compounds having potentially useful CDK inhibitory properties have been developed and reported in the literature. Flavopiridol is the first potent inhibitor of cyclin-dependent kinases (CDKs) to reach clinical trial. Flavopiridol has been found to potentiate synergistically the cytotoxic response of the conventional antineoplastic agents in a variety of cancer cell-lines. For example, sequential treatment of HCT116 colon cancer with docetaxel, flavopiridol and 5-fluorouracil has been reported in Acta Pharmacol Sin. 2006 October; 27(10):1375-81. Also, combined docetaxel and flavopiridol treatment for lung cancer cells has been reported in Radiother Oncol. 2004 May; 71(2):213-21 and for treatment of gastric cancer in Mol Cancer Ther. 2003 June; 2(6):549-55.
Although combinations of anticancer agents have been proven to have a significant advance in cancer treatment protocols, there are still several unmet needs and room for improvements for medications for the treatment of cancers, which are difficult to treat, or which have shown resistance to treatment with the conventional antineoplastic agents as a monotherapy. More particularly, the development of novel combination approach for delivering known anticancer agents having different mechanism of action would represent an important advance in the art. Although the protocol involving combination of anticancer agents having different mechanism of action may work in case of some combinations, it may not work in the same manner for other combination of anticancer agents and such combination may not always result in a combination having advantageous therapeutic effects. However, the present inventors have surprisingly found that a novel pharmaceutical combination of known anticancer agents comprising a cyclin dependant kinase inhibitor selected from compounds represented by formula I (as described herein) and a standard cytotoxic antineoplastic agent for the treatment of different cancers provides unexpectedly greater efficacy than when the anticancer agents are used alone.